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Book Details
Abstract
Cyclic peptides are increasingly employed as chemical tools in biology and drug discovery. They have gained a lot of interest as alternative sources of new drugs to traditional small molecules.
This book introduces cyclic peptides and provides a thorough overview of biosynthetic and fully synthetic approaches to their preparation. Following an introduction to cyclic peptides, biosynthetic and traditional chemical routes to cyclic peptides are reviewed. Due to their size, their synthesis is not trivial. Recent advances in the incorporation of novel structural units are presented in addition to how synthesis and biological methods can be combined. The chemical analysis of this molecular class is also discussed. Furthermore, chapters detail the progression of cyclic peptides as tools in biology and as potential drugs, providing a future vision of their importance.
In total, this book provides the reader with a comprehensive view of the state-of-the-art of cyclic peptides, from construction to possible clinical utility. This book will be an essential resource for students, researchers and scientists within industry in medicinal, bioorganic, natural product and analytical chemistry fields.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Cyclic Peptides: From Bioorganic Synthesis to Applications | i | ||
| Contents | v | ||
| Chapter 1 - An Introduction to Cyclic Peptides | 1 | ||
| 1.1 Of Peptides and Proteins (and Small Molecules) | 1 | ||
| 1.2 Conformational Constraints | 4 | ||
| 1.3 Cyclic Peptides as Pharmaceutical Agents | 7 | ||
| 1.4 End of the Prologue | 10 | ||
| References | 11 | ||
| Chapter 2 - The Biosynthesis of Cyclic Peptides – RiPPs – An Overview | 15 | ||
| 2.1 Introduction | 15 | ||
| 2.2 Cyanobactin Biosynthesis | 16 | ||
| 2.3 Lanthipeptides | 19 | ||
| 2.4 Thiopeptides | 20 | ||
| 2.5 Bottromycin | 21 | ||
| 2.6 Cyclic RiPPs from Plants: Cyclotides and Orbitides | 22 | ||
| 2.7 Cyclic RiPPs from Mushrooms: Amanitins and Dikaritins | 23 | ||
| 2.8 Conclusion and Outlook | 24 | ||
| References | 26 | ||
| Chapter 3 - Thioesterase Domain-mediated Macrocyclization of Non-ribosomal Peptides | 33 | ||
| 3.1 Introduction | 33 | ||
| 3.2 Types of Macrocyclic Non-ribosomal Peptide | 36 | ||
| 3.2.1 Cyclic Peptides | 36 | ||
| 3.2.2 Cyclic Depsipeptides | 36 | ||
| 3.2.3 Cyclic Thiodepsipeptides | 38 | ||
| 3.2.4 Cyclic Imino Peptides | 38 | ||
| 3.3 Biosynthesis of Macrocyclic NRPs | 38 | ||
| 3.3.1 NRP Biosynthesis | 39 | ||
| 3.3.2 Thioesterase Domains | 39 | ||
| 3.3.2.1 Type I TE Domains | 39 | ||
| 3.3.2.2 Type II TE Domains | 41 | ||
| 3.3.3 Other Termination Domains | 41 | ||
| 3.3.3.1 Reductase Domains | 42 | ||
| 3.3.3.2 Condensation(-like) Domains | 42 | ||
| 3.4 Mechanistic Insights into TE Domain-catalyzed Peptide Cyclization and Release | 43 | ||
| 3.4.1 Loading Step | 43 | ||
| 3.4.2 Releasing Step | 43 | ||
| 3.5 The Application of TE-I Domains for Synthesis of Cyclic Peptide Analogues | 44 | ||
| 3.5.1 Excised TE-I Domains | 45 | ||
| 3.5.2 Chemoenzymatic Approaches to Generate Natural Product Analogues | 47 | ||
| 3.6 Insight into the Interaction Between the TE-I and PCP Domains | 49 | ||
| 3.6.1 Interaction with the apo-PCP Domain | 49 | ||
| 3.6.2 Interaction with the holo-PCP Domain | 50 | ||
| 3.7 Summary and Outlook | 51 | ||
| Acknowledgements | 52 | ||
| References | 52 | ||
| Chapter 4 - The Biosynthetic Machinery and Its Potential to Deliver Unnatural Cyclic Peptides | 56 | ||
| 4.1 Non-natural Cyclic RiPPs – Expanding the Structural Space and Activities | 56 | ||
| 4.1.1 The Supplementation-based Incorporation Approach | 59 | ||
| 4.1.2 Genetic Code Expansion | 63 | ||
| 4.2 Cyclic NRPs with New-to-nature Modifications | 68 | ||
| 4.2.1 Precursor-directed Biosynthesis | 70 | ||
| 4.2.2 Mutasynthesis | 71 | ||
| 4.2.3 Combinatorial Biosynthesis and Domain Engineering | 75 | ||
| Acknowledgements | 78 | ||
| References | 78 | ||
| Chapter 5 - Modulation of Protein–Protein Interactions Using Cyclic Peptides | 86 | ||
| 5.1 Introduction | 86 | ||
| 5.2 Structure-based Design | 88 | ||
| 5.2.1 “Classic” Cyclic Peptides | 88 | ||
| 5.2.2 Secondary Structure Mimetics | 89 | ||
| 5.2.2.1 Cyclic Peptide Turns | 90 | ||
| 5.2.2.2 Cyclic Peptide β-strands | 90 | ||
| 5.2.2.3 Cyclic Helical Peptides | 92 | ||
| 5.3 In silico Approaches | 98 | ||
| 5.4 Fragment Screening and Combinatorial Approaches | 102 | ||
| 5.5 In vitro Methods | 104 | ||
| 5.5.1 Cellular Approaches | 107 | ||
| 5.5.1.1 Phage Display | 107 | ||
| 5.5.1.2 Yeast and Bacterial Display | 109 | ||
| 5.5.2 Non-cellular Approaches | 109 | ||
| 5.5.2.1 Ribosome Display and mRNA Display | 109 | ||
| 5.5.2.2 CIS Display | 111 | ||
| 5.6 Final Remarks | 112 | ||
| Acknowledgements | 113 | ||
| References | 113 | ||
| Chapter 6 - Biology and Synthesis of the Argyrins | 122 | ||
| 6.1 Introduction | 122 | ||
| 6.2 Biological Activity | 123 | ||
| 6.3 Synthesis | 128 | ||
| 6.3.1 Biosynthesis | 128 | ||
| 6.3.2 Ley’s Total Synthesis | 129 | ||
| 6.3.3 Kalesse’s Total Synthesis | 131 | ||
| 6.3.4 Jiang’s Total Syntheses | 131 | ||
| 6.3.5 Chan’s Approach to Argyrin Analogues | 136 | ||
| References | 139 | ||
| Chapter 7 - Peptide Cross-links Catalyzed by Metalloenzymes in Natural Product Biosynthesis | 141 | ||
| 7.1 Introduction | 141 | ||
| 7.2 Penicillin Antibiotics | 142 | ||
| 7.2.1 Penicillin Biosynthesis | 143 | ||
| 7.2.2 Isopenicillin N Synthase | 144 | ||
| 7.2.3 IPNS Mechanism | 144 | ||
| 7.2.4 Impact of Penicillin and Its Biosynthesis | 147 | ||
| 7.3 Glycopeptide Antibiotics | 147 | ||
| 7.3.1 Oxy Enzymes in Glycopeptide Biosynthesis | 147 | ||
| 7.3.2 Structural Characterization of Oxy Enzymes | 149 | ||
| 7.3.3 Mechanistic Proposals for Oxy Enzymes | 150 | ||
| 7.4 Radical SAM Enzymes Involved in Intramolecular RiPP Cross-links | 153 | ||
| 7.4.1 PQQ | 154 | ||
| 7.4.2 Sactipeptides | 154 | ||
| 7.4.3 Streptide | 155 | ||
| 7.4.4 Mechanisms of RiPP Cyclizations by Radical SAM Enzymes | 155 | ||
| 7.5 Conclusions | 158 | ||
| Acknowledgements | 159 | ||
| References | 159 | ||
| Chapter 8 - Double-click Stapled Peptides for Inhibiting Protein–Protein Interactions | 164 | ||
| 8.1 Introduction | 164 | ||
| 8.2 Non-proteogenic Amino Acid Synthesis | 167 | ||
| 8.3 Peptide Sequence Optimization and Use of Functionalized Staple Linkages for Modulating the Cellular Activity of Stapled Pepti... | 168 | ||
| 8.4 Metal-free Strain-promoted Peptide Stapling | 170 | ||
| 8.5 Constrained Macrocyclic Non-α-helical Peptide Inhibitors | 172 | ||
| 8.5.1 Design of Macrocyclic Peptide Inhibitors to Target the Substrate-recognition Domain of Tankyrase and Antagonize Wnt Signali... | 173 | ||
| 8.5.2 Development of Cell-permeable, Non-helical, Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Can... | 178 | ||
| Acknowledgements | 183 | ||
| References | 183 | ||
| Chapter 9 - Libraries of Head-to-tail Peptides | 188 | ||
| 9.1 Introduction | 188 | ||
| 9.2 Chemically Synthesized Libraries | 190 | ||
| 9.2.1 Synthesis and Deconvolution of Diverse Linear Peptide Libraries | 190 | ||
| 9.2.2 Head-to-tail Cyclization of Peptide Libraries | 191 | ||
| 9.2.3 Deconvolution Strategies for Head-to-tail Cyclic Peptide Libraries | 194 | ||
| 9.3 Genetically Derived Libraries | 195 | ||
| 9.3.1 SICLOPPS | 196 | ||
| 9.3.2 Genetically Encoded Cyclic Peptide Library Production In vitro | 199 | ||
| 9.4 Conclusion | 202 | ||
| References | 203 | ||
| Chapter 10 - An Introduction to Bacterial Lasso Peptides | 206 | ||
| 10.1 An Introduction to Bacterial Lasso Peptides | 206 | ||
| 10.2 Investigation of Lasso Peptide Structures | 214 | ||
| 10.3 Biological Functions of Lasso Peptides | 218 | ||
| 10.4 Lasso Peptides as Scaffolds for Drug Development | 219 | ||
| References | 221 | ||
| Chapter 11 - Biological Synthesis and Affinity-based Selection of Small Macrocyclic Peptide Ligands | 225 | ||
| 11.1 Introduction | 225 | ||
| 11.2 Selection of Cyclic Peptides from Libraries Composed of Canonical Amino Acids | 227 | ||
| 11.2.1 Head-to-tail Peptide Cyclization Using Split-inteins (SICLOPPS) | 227 | ||
| 11.2.2 Phage/Phagemid Display | 231 | ||
| 11.2.3 mRNA Display, cDNA Display and Ribosome Display | 234 | ||
| 11.3 Broadening Library Chemical Diversity | 235 | ||
| 11.3.1 Genetic Code Expansion | 236 | ||
| 11.3.2 Genetic Code Reprogramming in Reconstituted Translation Systems | 237 | ||
| 11.3.3 Enzymatic Aminoacylation by Natural AARSs | 238 | ||
| 11.3.4 Aminoacylation of tRNAs Catalyzed by Flexizymes | 240 | ||
| 11.3.5 Further Developments | 242 | ||
| 11.4 Genetically Engineered Selections of Target-binding Macrocyclic Peptides | 243 | ||
| 11.4.1 Selections Involving Genetic Code Expansion | 244 | ||
| 11.4.2 Selections Involving ARS-mediated Genetic Code Reprogramming | 244 | ||
| 11.4.3 Selections Involving FIT-mediated Genetic Code Reprogramming | 245 | ||
| 11.5 Summary | 248 | ||
| Acknowledgements | 249 | ||
| References | 249 | ||
| Chapter 12 - Mass Spectrometric Analysis of Cyclic Peptides | 255 | ||
| 12.1 Classification of Cyclic Peptides | 255 | ||
| 12.2 Nomenclature | 256 | ||
| 12.3 Strategies for Structural Analysis | 258 | ||
| 12.4 Ionization Methods | 259 | ||
| 12.5 Fragmentation Methods | 262 | ||
| 12.5.1 Threshold Dissociations | 262 | ||
| 12.5.2 Ion–Electron Dissociations (ExD) | 262 | ||
| 12.5.3 MALDI-related Methods | 263 | ||
| 12.6 Application of Tandem Mass Spectrometry to Cyclic Peptides | 263 | ||
| 12.6.1 General Procedure | 264 | ||
| 12.6.2 Metal Complexation | 264 | ||
| 12.6.3 Ion–Electron Dissociation (ExD) for Cyclic Peptides | 265 | ||
| 12.6.4 Post-source Decay and In-source Decay | 268 | ||
| 12.6.5 Ion Mobility-mass Spectrometry of Cyclic Peptides | 270 | ||
| 12.6.6 Quantification | 271 | ||
| 12.7 Conclusions | 273 | ||
| References | 273 | ||
| Chapter 13 - Experimental and Computational Approaches to the Study of Macrocycle Conformations in Solution | 280 | ||
| 13.1 Introduction | 280 | ||
| 13.2 Overview of Conformation Elucidation Techniques | 281 | ||
| 13.2.1 X-ray Crystallography | 281 | ||
| 13.2.2 Purely Computational Methods | 282 | ||
| 13.2.3 Hybrid Methods | 282 | ||
| 13.3 NMR Assignment and General Considerations | 283 | ||
| 13.3.1 Introduction | 283 | ||
| 13.3.2 General Consideration: Solvent Systems | 283 | ||
| 13.3.3 Determining 2D Structure: Primary Sequence | 284 | ||
| 13.4 Conformational Information from NMR | 285 | ||
| 13.4.1 Introduction | 285 | ||
| 13.4.2 3J Correlations | 285 | ||
| 13.4.3 Through-space Couplings | 286 | ||
| 13.4.4 Establishing Cis–Trans Relationships for 3° Amides | 287 | ||
| 13.4.5 Residual Dipolar Couplings (RDCs) | 289 | ||
| 13.4.6 Measures of Intramolecular Hydrogen Bonding | 289 | ||
| 13.4.6.1 Temperature Shift Analysis | 290 | ||
| 13.4.6.2 H–D Exchange | 291 | ||
| 13.5 Generation of NMR-informed Solution Conformations | 291 | ||
| 13.5.1 Unrestrained Conformation Generation and Sampling | 292 | ||
| 13.5.1.1 Sampling | 292 | ||
| 13.5.1.2 Energetic Comparisons | 293 | ||
| 13.5.2 Naïve Sampling and NMR-best Fit Selection | 293 | ||
| 13.5.2.1 Single Conformer Fitting | 293 | ||
| 13.5.2.2 Fitting NMR Data to Conformational Ensembles | 294 | ||
| 13.5.2.3 NMR Chemical Shift-based Methods | 295 | ||
| References | 295 | ||
| Chapter 14 - Trends in Cyclotide Research | 302 | ||
| 14.1 Introduction | 302 | ||
| 14.2 Trends in the Growth of the Cyclotide Field | 303 | ||
| 14.3 Categories of Cyclotide Research: an Analysis | 304 | ||
| 14.3.1 Peptide-based Discovery | 306 | ||
| 14.3.2 Gene-based Discovery and Cyclotide Gene Regulation | 306 | ||
| 14.3.3 Analysis | 309 | ||
| 14.3.4 Structures, Folding and Dynamics | 312 | ||
| 14.3.5 Bioactivity | 315 | ||
| 14.3.6 Biosynthesis | 315 | ||
| 14.3.7 Synthesis | 316 | ||
| 14.3.8 Drug Design and Protein Engineering Applications | 316 | ||
| 14.3.9 Membrane Binding, Cell Penetration and Toxicity | 317 | ||
| 14.4 Reviews | 320 | ||
| 14.5 Conclusions | 320 | ||
| Acknowledgements | 323 | ||
| References | 323 | ||
| Chapter 15 - Cyclic Peptides – A Look to the Future | 340 | ||
| 15.1 Introduction | 340 | ||
| 15.1.1 Advantages of Cyclic Peptides | 341 | ||
| 15.2 Synthetic and Biosynthetic Approaches to Cyclic Peptides | 342 | ||
| 15.2.1 Synthetic Methods for Cyclization | 342 | ||
| 15.2.2 Biochemical Methods for Cyclization | 346 | ||
| 15.3 PK/ADMET Properties of Cyclic Peptides | 349 | ||
| 15.3.1 Introduction | 349 | ||
| 15.3.2 Prediction of PK/ADMET Properties of Cyclic Peptides: The New ‘Beyond Rule of 5’ Guidelines | 349 | ||
| 15.3.3 Backbone Modifications Affecting PK and ADMET | 352 | ||
| 15.4 Prediction of Structures of Cyclic Peptides | 354 | ||
| 15.4.1 Conformational Search Algorithms | 355 | ||
| 15.4.2 Molecular Dynamics Simulations | 356 | ||
| 15.4.3 Force Fields | 358 | ||
| 15.4.4 Predicting Whether Peptides Will Cyclize | 359 | ||
| 15.4.5 Conclusions | 361 | ||
| 15.5 Binding of Cyclic Peptides to Targets | 361 | ||
| 15.6 Hybrid Systems to Generate Diversity in Cyclic Peptides | 363 | ||
| 15.7 Conclusions | 365 | ||
| References | 366 | ||
| Subject Index | 374 |